The article discusses the role of TNF superfamily members in T-cell function and their potential therapeutic applications. It focuses on four specific ligand-receptor interactions: OX40 ligand (OX40L) and OX40, 4-1BB ligand and 4-1BB, CD70 and CD27, and TL1A and death receptor 3. These interactions are crucial for regulating T-cell responses, including co-stimulation, cell survival, and cytokine production. The article highlights the therapeutic potential of manipulating these interactions to treat inflammatory conditions, autoimmunity, and cancer. Neutralizing antibodies and Fc fusion proteins that inhibit these interactions have shown promise in preclinical studies, reducing disease severity in various models. Additionally, agonist antibodies targeting 4-1BB have demonstrated antitumor effects by promoting T-cell responses. The article also explores the complex signaling pathways involved in these interactions and the potential for using RNA aptamers and complement-dependent cytotoxicity in therapy. Overall, the TNF superfamily members discussed in this review offer significant therapeutic opportunities, but further research is needed to optimize their use in clinical settings.The article discusses the role of TNF superfamily members in T-cell function and their potential therapeutic applications. It focuses on four specific ligand-receptor interactions: OX40 ligand (OX40L) and OX40, 4-1BB ligand and 4-1BB, CD70 and CD27, and TL1A and death receptor 3. These interactions are crucial for regulating T-cell responses, including co-stimulation, cell survival, and cytokine production. The article highlights the therapeutic potential of manipulating these interactions to treat inflammatory conditions, autoimmunity, and cancer. Neutralizing antibodies and Fc fusion proteins that inhibit these interactions have shown promise in preclinical studies, reducing disease severity in various models. Additionally, agonist antibodies targeting 4-1BB have demonstrated antitumor effects by promoting T-cell responses. The article also explores the complex signaling pathways involved in these interactions and the potential for using RNA aptamers and complement-dependent cytotoxicity in therapy. Overall, the TNF superfamily members discussed in this review offer significant therapeutic opportunities, but further research is needed to optimize their use in clinical settings.